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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Mini Review ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)) Shian-Yang Peng, Shih-Yeh Lin, Hey-Chi Hsu Department of General Education, National Taipei College of Nursing, Taipei 100, Taiwan, Republic of China (SYP); Graduate Institute of Pathology, College of Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, Republic of China (SYL); Department of Pathology, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan, Republic of China (HCH) Published in Atlas Database: December 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/ASPMID44463ch1q31.html DOI: 10.4267/2042/44847 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology spindle) homolog, microcephaly associated (Drosophila)); ZBTB41 (1q31.3) (zinc finger and BTB domain containing 41); LOC127011 (1q31.3) (similar to ATPase, H+ transporting, lysosomal accessory protein 2); MRPS21P3 (1q31.2) (mitochondrial ribosomal protein S21 pseudogene 3); CRB1 (1q31q32.1) (crumbs homolog 1 (Drosophila)); C1orf218 (1q31.3) (chromosome 1 open reading frame 218); DENND1B (1q31.3) (DENN/MADD domain containing 1B); LOC730232 (1q31.3) (similar to eukaryotic translation elongation factor 1 alpha 1); LOC100129017 (1q31.3) (hypothetical LOC100129017); C1orf53 (1q31.3) (chromosome 1 open reading frame 53); LHX9 (1q31-q32) (LIM homeobox 9); LOC647195 (1q31.3) (hypothetical LOC647195); NEK7 (1q31.3) (NIMA (never in mitosis gene a)-related kinase 7). Identity Other names: ASP; Calmbp1; DKFZp686N06184; FLJ10517; FLJ10549; FLJ43117; MCPH5 HGNC (Hugo): ASPM Location: 1q31.3 Local order: Several genes flanking ASPM arranged by an order of centromere to telomere are: KCNT2 (1q31.3) (potassium channel, subfamily T, member 2); CFH (1q32) (complement factor H); CFHR3 (1q32) (complement factor H-related 3); CFHR1 (1q32) (complement factor H-related 1); CFHR4 (1q32) (complement factor H-related 4); CFHR2 (1q31-q32.1) (complement factor H-related 2); CFHR5 (1q22-q23) (complement factor H-related 5); F13B (1q31-q32.1) (coagulation factor XIII, B polypeptide); ASPM (1q31) (asp (abnormal Genomic diagram of ASPM gene. Exons are represented by boxes on the diagram. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9) 861 ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)) Peng SY, et al. human embryo tissues (brain, bladder, colon, heart, liver, lung, skeletal muscle, skin, spleen and stomach), and in adult tissues except for the adult brain, but with much lower amount. ASPM isoforms were generated by alternative splicing. The brain-specific isoform, main ASPM isoform corresponds to a 3477 amino acid residue protein (410 kDa) containing 81 IQ motifs. Alternatively spliced human ASPM variants code for different numbers of IQ domains. Two major ASPM transcripts with sizes of 10.3 and 5.7 kb were identified in all tissues analyzed. The spliced variants of ASPM with variable sizes were also detected in fetus tissue. DNA/RNA Description ASPM, maps to NC_000001.10 in human genome, contains 28 exons with a 10,434 base pairs ORF (NCBI GenBank accession number AF509326), spanning a region of 62,568 base pairs at chromosome 1q31. Transcription ASPM encodes a 10906 bps mRNA, (NM_018136.4), in a telomeric to centromeric orientation and the coding region is from 258 bp to 10961bp (10434 bp). 5' part of exon 1 and 3' part of exon 28 are non-coding. The 28 exons of ASPM mRNA are 554, 144, 1480, 105, 147, 246, 68, 142, 131, 176, 146, 86, 222, 208, 143, 129, 195, 4755, 167, 97, 210, 150, 192, 193, 155, 177, 170, 300 base pairs, respectively. Localisation ASPM protein, a component of the mitotic spindle, localizes to the centrosome in interphase and to the spindle poles from prophase through telophase. Pseudogene Function None. ASPM is a spindle pole/centrosome protein, essential for neurogenic mitosis and possibly controlling the fate-switch to asymmetric cell division through the position of the centrosome at mitosis. The brainspecific main ASPM isoform protein appears to be pivotal for the expansion of cerebral cortical size. Other spliced variants contain different IQ domains or lacking both CH domains and a part of the IQ motifs may be potentially with different functions. One of the smaller proteins detected in cell extracts may be the ASPM product required for mitosis by all dividing cells. Protein Description The 10434 bps ORF of ASPM mRNA translates a 3477 amino acid protein with a calculated molecular weight of 409.8 kDa. The main ASPM isoform protein, from N-terminal, begins with a microtubule binding domain, followed by two calponin homology (CH) domains, which are possibly responsible for transportation of the ASPM protein to the spindle poles. The third part is IQ (I for isoleucine, Q for glutamine) repeats region which is the calmodulin binding domains. The numbers of IQ repeats are identified up to 81, at position 1273 to 3243. The C-terminal of ASPM is an armadillo-like domain of unknown function. Homology According to protein identities compared with Human ASPM: Pan troglodytes: ASPM; (3443/3477, 99%) Canis lupus familiaris: ASPM; (2738/3392, 80%) Bos taurus: ASPM; (2557/3484, 73%) Mus musculus: Aspm; (1882/2948, 63%) Rattus norvegicus: Aspm; (1851/2939, 62%) Danio rerio: aspm; (1390/3554, 39%) Expression ASPM transcripts were detected in a variety of ASPM protein contains 2 calponin homology (CH) domains and 81 IQ repeats domain. Total 81 distinct IQ motifs were found at position 1273 to 3243. Numbers indicate the amino acid numbers. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9) 862 ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)) Peng SY, et al. Mutations Mutation of ASPM in MCPH. According to Nicholas et al. 2009, all reported autosomal recessive primary microcephaly (MCPH) mutations in ASPM have been presented in this table by different kind of mutations, including nonsense mutations, deletions, insertions and mutations in the splicing region. The reference sequence of mutation sites is according to NM_018136.3. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9) 863 ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)) knockdown also inhibits cell growth of U87-EGFRvIII cells (glioblastoma cells) and the low passage explant culture from a glioblastoma patient. Those result suggesting that ASPM is a potential molecular target in glioblastoma that resulting in the overexpression of ASPM in glioblastoma. Implicated in Primary autosomal recessive microcephaly (MCPH) Note Primary autosomal recessive microcephaly is a neurodevelopment disorder due to the consequence of deficient neurogenesis within the neurogenic epithelium, resulting in congenital microcephaly (reduced brain size) and mental retardation. MCPH is the consequence of impairment in mitotic spindle regulation in cortical progenitors due to mutations in ASPM. Homozygous mutations in the ASPM gene, located at MCPH5 locus on chromosome 1q31, are the most common cause of MCPH particularly in the Pakistani population. ASPM mutations are restricted to individuals with an MCPH, no defects other than microcephaly are found in patients carrying mutations in this gene. So far, the phenotypic differences in people with different versions of these genes were not found. Cancers of the uterus and ovary Note From high-density oligonucleotide microarrays and using quantitative real-time RT-PCR, ASPM is found more highly expressed in cancers of the uterus and ovary when compared with their normal endometrium counterparts. References Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG. ASPM is a major determinant of cerebral cortical size. Nat Genet. 2002 Oct;32(2):316-20 Bond J, Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG. Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet. 2003 Nov;73(5):1170-7 Hepatocellular carcinoma Note ASPM, a component of the mitotic spindle, is shown to express in many human malignant cells nearly and all transformed human cell lines, suggesting that ASPM play an important role in cell proliferation in tumorigenesis. ASPM mRNA was overexpressed in human hepatocellular carcinoma (HCC), but was very low or undetectable in adult liver, and in benign hepatic tumors, such as hepatocellular adenoma and focal nodular hyperplasia. The overexpression of ASPM correlated with higher-grade (grade II-IV), high-stage (stage IIIA-IV which had vascular invasion) and poor prognosis of HCC. In addition, ASPM overexpression is the most important molecular factor associated with ETR (early tumor recurrence) (intrahepatic tumor recurrence and/or distant metastasis within 12 months after HCC tumor resection), and could be used as a molecular marker predicting enhanced invasive/metastatic potential of HCC. Kumar A, Blanton SH, Babu M, Markandaya M, Girimaji SC. Genetic analysis of primary microcephaly in Indian families: novel ASPM mutations. Clin Genet. 2004 Oct;66(4):341-8 Kouprina N, Pavlicek A, Collins NK, Nakano M, Noskov VN, Ohzeki J, Mochida GH, Risinger JI, Goldsmith P, Gunsior M, Solomon G, Gersch W, Kim JH, Barrett JC, Walsh CA, Jurka J, Masumoto H, Larionov V. The microcephaly ASPM gene is expressed in proliferating tissues and encodes for a mitotic spindle protein. Hum Mol Genet. 2005 Aug 1;14(15):2155-65 Shen J, Eyaid W, Mochida GH, Al-Moayyad F, Bodell A, Woods CG, Walsh CA. ASPM mutations identified in patients with primary microcephaly and seizures. J Med Genet. 2005 Sep;42(9):725-9 Zhong X, Liu L, Zhao A, Pfeifer GP, Xu X. The abnormal spindle-like, microcephaly-associated (ASPM) gene encodes a centrosomal protein. Cell Cycle. 2005 Sep;4(9):1227-9 Gul A, Hassan MJ, Mahmood S, Chen W, Rahmani S, Naseer MI, Dellefave L, Muhammad N, Rafiq MA, Ansar M, Chishti MS, Ali G, Siddique T, Ahmad W. Genetic studies of autosomal recessive primary microcephaly in 33 Pakistani families: Novel sequence variants in ASPM gene. Neurogenetics. 2006 May;7(2):105-10 Glioblastoma Horvath S, Zhang B, Carlson M, Lu KV, Zhu S, Felciano RM, Laurance MF, Zhao W, Qi S, Chen Z, Lee Y, Scheck AC, Liau LM, Wu H, Geschwind DH, Febbo PG, Kornblum HI, Cloughesy TF, Nelson SF, Mischel PS. Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target. Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7 Note ASPM is essential for normal mitotic spindle function in embryonic neuroblasts, and is recognized as a critical regulator of brain size, it may play a role in promoting neuroblast proliferation. Using gene coexpression module in glioblastoma, ASPM was identified as a key gene of glioblastoma, its overexpression was demonstrated in glioblastoma relative to normal brain. siRNA-mediated ASPM knockdown inhibits neural stem cell self renewal and turn forward neural stem cell differentiation. ASPM Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9) Peng SY, et al. Gul A, Tariq M, Khan MN, Hassan MJ, Ali G, Ahmad W. Novel protein-truncating mutations in the ASPM gene in families with autosomal recessive primary microcephaly. J Neurogenet. 2007 Jul-Sep;21(3):153-63 Paramasivam M, Chang YJ, LoTurco JJ. ASPM and citron kinase co-localize to the midbody ring during cytokinesis. Cell Cycle. 2007 Jul 1;6(13):1605-12 864 ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)) Peng SY, et al. Lin SY, Pan HW, Liu SH, Jeng YM, Hu FC, Peng SY, Lai PL, Hsu HC. ASPM is a novel marker for vascular invasion, early recurrence, and poor prognosis of hepatocellular carcinoma. Clin Cancer Res. 2008 Aug 1;14(15):4814-20 landscape of ASPM mutations in primary microcephaly. J Med Genet. 2009 Apr;46(4):249-53 Nicholas AK, Swanson EA, Cox JJ, Karbani G, Malik S, Springell K, Hampshire D, Ahmed M, Bond J, Di Benedetto D, Fichera M, Romano C, Dobyns WB, Woods CG. The molecular Peng SY, Lin SY, Hsu HC. ASPM (asp (abnormal spindle) homolog, microcephaly associated (Drosophila)). Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9):861-865. Atlas Genet Cytogenet Oncol Haematol. 2010; 14(9) This article should be referenced as such: 865